WO1996025158A1

WO1996025158A1 - Medicinal composition containing azulene derivative and process for producing the same

Info

Publication number: WO1996025158A1
Application number: PCT/JP1996/000327
Authority: WO
Inventors: Yoshimi Hashimoto; Yasushi Egawa; Hideyuki Kishimoto
Original assignee: Yamanouchi Pharmaceutical Co., Ltd.
Priority date: 1995-02-16
Filing date: 1996-02-15
Publication date: 1996-08-22
Also published as: AU4675696A

Abstract

A stable medicinal composition containing aldioxa and sodium 1,4-dimethyl-7-isopropylazulene-3-sulfonate (GASN) in the form of granules prepared by wet granulation; and a medicinal composition containing a histamine H2 receptor antagonist, GASN and aldioxa,wherein at least GASN and aldioxa are contained in the granules prepared by wet granulation.

Description

Description Pharmaceutical composition containing azulene derivative and method for producing the same

The present invention relates to a stable pharmaceutical composition of sodium 1,4-dimethyl-7-isopropylazulene-13-sulfonate and a method for producing the same.

The present invention also relates to a histamine H2 receptor antagonist-containing pharmaceutical composition having excellent efficacy and stability for treating and preventing gastrointestinal diseases and a method for producing the same. Background art

1,4-Dimethyl-17-isopropylazulene-3-sodium sulfonate (hereafter abbreviated as GASN) is the asteraceous plant force native to southern and eastern Europe.

(Matricaria Chamomill L.) is a derivative of guaiazulene (chemical name: 1,4-dimethinoleh 7-isopropinoleazulene). Guaiazulene has anti-inflammatory and anti-ulcer properties, and is insoluble in liquid at room temperature.Water-soluble GAS N is widely used and has high safety, so it is used as a solid preparation such as tablets and granules. It is widely used for medical, medical and pharmaceutical products.

However, GASN was not sufficiently stable as a drug, and could not be stored for a long period of time even if the drug was manufactured in the usual way. This is due to the GASN force, 'sublimation', and the gradual decomposition by light and oxygen in ^.

Therefore, many studies have been conducted to stabilize GASN. One example is the stabilization of amino acids with a weak salt (JP-A-49-11219), and the stabilization by rapidly distilling off the solvent by spray drying or fine drying.

(JP-A-58-154548), stabilization with edetic acid and its salts (Japanese Patent Laid-Open Publication No. Hei 1-112126), stabilization with calcium gayate (JP-A-4-1243382), stabilization with sucralfate (JP-A-6-227972). However, even with these measures, it has been difficult to maintain the stability of the drug in the potentially long-term distribution process.

On the other hand, aldioxa (chemical name: dihydroxy [(2-hydroxy-5-oxo-2-imidazoline-141-yl) ureido] aluminum) directly acts on the gastric mucosa to promote granulation formation, antacid and anti-pepsin. It is widely used as a medical or over-the-counter drug alone or in combination as a preventive and therapeutic agent for gastric 'duodenal ulcer, acute and chronic gastritis. In addition to the disclosure that it contributes to the stability of other pharmaceutical compounds, there have been reports suggesting that it also contributes to the stability of other drugs.

Histamine H 2 receptor antagonists inhibit gastric acid secretion by antagonizing hissamine in the histomin H2 receptors in gastric parietal cells, and mainly treat gastric and duodenal ulcers and acute and chronic gastritis It is widely used as a therapeutic agent for gastrointestinal diseases. A combination of a hissamine H2 receptor antagonist and another drug is also being studied.For example, Japanese Patent Application Laid-Open No. Sho 58-208220 discloses a hissamine H2 receptor antagonist and aldioxa. An agent for treating peptic ulcer and preventing relapse and recurrence as an active ingredient is disclosed.

Drugs for the treatment and prevention of gastrointestinal disorders such as gastric ulcers, acute and chronic gastritis are in demand not only as medical drugs but also as over-the-counter drugs, and there is a need for the development of better drugs. ing. Disclosure of the invention

The present inventor has found that a stable GASN-containing preparation can be produced by blending GDASN with aldioxa and performing wet granulation.

Further, the present invention provides a pharmaceutical composition comprising a histamine H2 receptor antagonist, GASN and argioxa, wherein at least GASN and argioxa are contained in a wet-granulated granule. By using a certain histamine H2 receptor antagonist-containing pharmaceutical composition, GASN is stable as a commercial drug due to stabilization of GASN, and has gastrointestinal tract diseases such as gastric ulcer and acute / chronic gastritis. The present inventors have found that it is possible to provide a pharmaceutical composition having remarkably excellent therapeutic and preventive effects on the present invention, and have completed the present invention. That is, the present invention is a GASN-containing pharmaceutical composition obtained by blending GASN and argioxa and granulating the mixture by wet granulation.

Further, the present invention is a method for producing a GASN-containing pharmaceutical composition, which comprises mixing GASN and ardioxa and granulating the mixture by wet granulation.

Further, the present invention relates to a pharmaceutical composition containing a histamine H2 receptor antagonist, GASN and argioxa, wherein at least GASN and argioxa are contained in a granulated product * standing by a wet granulation method. A pharmaceutical composition comprising a hismin H2 receptor antagonist.

Furthermore, the present invention further provides a granulation force by mixing GASN, argioxa and a histamine H2 receptor antagonist and granulating by wet granulation, or a mixture of GASN and argioxa and granulating by wet granulation. is a manufacturing method of the His evening Min H ² receptor antagonist containing pharmaceutical composition which is to be blended with His evening Min H ² receptor antagonists.

The reference of the GASN-containing pharmaceutical composition of the present invention includes a pharmaceutical composition comprising GASN and argioxa, a granulated product obtained by a wet granulation method, and wherein the granulated product comprises GASN and argioxa. By adopting such a configuration, GASN and argioxa can be uniformly dispersed in the particles of the granulated material, and as a result, GASN can be stabilized for a long period of time. is there. In other words, the GASN-containing pharmaceutical composition of the present invention contains one or more wet-granulated particles, each particle containing GASN, and an aldioxa for stabilizing GASN, and It can be said that a pharmaceutical composition is characterized in that GASN and aldoxane power are uniformly dispersed within the polymer. It has been pointed out that simply mixing GASN and argioxa does not achieve the goal of GASN stability.

Moreover, Toko filtration to as hiss evening Min H ² receptor antagonist containing pharmaceutical compositions of the present invention, shall apply in pharmaceutical compositions containing a histamine H2 receptor antagonist and GASN and Arujiokisa, the pharmaceutical composition Is characterized by containing at least a granulated product of GASN and argioxa granulated by a wet granulation method. By adopting such a configuration, GASN and argioxa are uniformly dispersed in the particles of the granulated product, and the mixture with this and a hissamine H2 receptor antagonist stabilizes GASN for a long period of time. This In addition, GASN has the effect of enhancing gastric mucosal protective factor, and the effect of argioxa on the enhancement of gastric mucosal protective factor and gastric acid of histamine H2 receptor antagonist when argioxa is used. It has a synergistic effect on the treatment and prevention of gastrointestinal diseases such as gastric ulcer and acute and chronic gastritis due to its secretion inhibitory effect. In other words, the histamine H2 receptor antagonist-containing pharmaceutical composition contains one or more wet-granulated particles, each of which contains at least GASN and an algioxa for stabilizing GASN. It is assumed that GASN and ardioxa are uniformly dispersed in each particle, and that the histamine H2 receptor antagonist is contained as a component of the composition inside or outside the particle. It can be said to be a pharmaceutical composition.

Hereinafter, the present invention will be described in detail.

In the present invention, the term “granulation” simply refers to granules (ie, particles) having a substantially uniform shape using a drug substance having various shapes such as a powder, an agglomerate, a solution, or a melt. It means the whole process of making, and "granulating" in a particular way means to make grains of almost uniform shape and size in that particular way.

Therefore, the “wet granulation method” applied to the GASN-containing pharmaceutical composition and the histamine H 2 receptor antagonist-containing pharmaceutical composition of the present invention refers to granulation by adding a liquid binder to a drug substance raw material powder ( In other words, a method of making grains of almost uniform shape and size).

The “wet granulation method” includes everything included in the above definition. Specifically, for example, (1) a binder solution is added to the raw material powder, the mixture is kneaded, and the combined material is squeezed onto a screen and extruded. Extrusion granulation method using extrusion granulation equipment (eg, cylindrical granulator FG type, manufactured by Fukae Kogyo Co., Ltd. Twin Dome Gran, manufactured by Fuji Padal Co., Ltd.), ② Speed mill (Showa engineering) ±), power mill (Danoretone ¾ ±), etc. to crush the wet mixture to a certain size by crushing the wet mixture. □ Agitation granulation method in which granulation is performed while mixing and agitating using a Henshenole mixer (Rheinstahl Henshel AG tt), a vertical mixer, etc., a ¾ core fluidized granulation device (eg, manufactured by Freund Corporation), Mouth Processor (Eromatic Judges Sangyo), make spherical particles by either or coating spraying the binder raw material is rolled using Marumerizer one (Fuji Paudarune ± ^) or the like Tumbling granulation, spray drier for spraying liquid or suspension and drying sprayed droplets

(For example, Okawara ϊΐα: Machinery ± ¾), 噴霧 A layer of raw material powder is formed by air flow, and a binder solution is sprayed into the layer while drying, and particles adhere and aggregate by liquid crosslinking. This method uses a fluidized-bed granulator (eg, Spiral Flow, manufactured by Freund Sangyo Co., Ltd .; Nummarmerizer I, Fuji Baudal).

The “GASN-containing pharmaceutical composition” of the present invention is a pharmaceutical composition containing GASN and argioxa, which is produced through a granulation step by a wet granulation method. Granules and granules include all forms including wet granulation processes such as ^! Life, tablets, pills, cheabnole tablets and capseno ^.

Further, the “pharmaceutical composition containing a histamine H 2 receptor antagonist” of the present invention contains a histamine H 2 receptor antagonist, GASN and argioxa, and is manufactured through a granulation step by a wet granulation method. A pharmaceutical composition comprising a granulated product containing at least GASN and argioxa, which is obtained by granulating a histamine H2 receptor antagonist, GASN and argioxa by wet granulation. Alternatively, various formulations may be prepared by blending GASN and aldioxa and granulating them by a wet granulation method, and blending a histamine H 2 receptor antagonist. Examples of the pharmaceutical composition of the pharmaceutical composition include fine granules and granules, as well as tablets, pills, chew nore tablets and capsules. At least GASN and argioxa are blended and the granulation step by wet granulation is carried out. All formulation forms which are included in the present invention are included.

The compounding amount of the components of the GASN-containing pharmaceutical composition or the histamine H2 receptor antagonist-containing pharmaceutical composition of the present invention is from 0.01 parts by weight to 250 parts by weight of Ardioxa per 1 part by weight of GASN. Force <preferred. If the amount is less than 0.01 parts by weight, GASN may not be sufficiently stabilized, and there may be a case.

Further, it is preferable that the content of Aldioxa is 0.5 to 100 parts by weight based on 1 part by weight of GASN. The desired effect can be achieved even if the amount of argioxa compounded for stabilizing GAS N is less than or equal to the amount of drug effect. The GASN-containing pharmaceutical composition or the histamine H2 receptor antagonist-containing pharmaceutical composition of the present invention preferably contains, at a daily dose, 1.2 mg to 6 mg of GASN and 0.6 mg to 60 Omg of aldioxa. contains.

The hiss evening Min H 2 receptor antagonist is a component of the histamine H ² receptor antagonist containing pharmaceutical compositions of the present invention, for example famotidine, Ranichijinku cimetidine, Rokisajin, including but nizatidine, particularly limited to It does not do. Also included are the pharmaceutically acceptable salts thereof, for example, hydrochloride, hydrobromide, iodine bT citrate, sulfate, fumarate, maleate, succinate, liquor, picrine Salts formed with inorganic or organic acids, such as acid salts. Among the Hisamine H2 receptor antagonists, particularly preferred is famotidine, which has a low dose and has a potent and long-term effect on suppressing gastric acid secretion.

In the histamine H2 receptor antagonist-containing pharmaceutical composition of the present invention, the amount of the histamine H2 receptor antagonist can usually be used in a clinically acceptable amount. There are also various drugs for hissamine H2 receptor antagonists, each of which has an appropriate dose. For example, taking famotidine as an example, it is strongly preferable to use 0.5 mg to 500 mg per dose, more preferably 1 mg to 10 Omg.

The most preferred embodiment of the histamine H2 receptor antagonist-containing pharmaceutical composition of the present invention is a daily dosage of 1 mg to 100 mg of famotidine, 1.2 mg to 6 mg of GASN, and 0.6 mg to 600 mg of argioxa. Contains mg.

Examples of the binder used in the wet granulation of the present invention include hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol and the like, and the like. It does not matter if the binder is used for wet granulation.

The GASN-containing pharmaceutical composition or the histamine H2 receptor antagonist-containing pharmaceutical composition of the present invention may contain, in addition to the above, additives suitable for formulation.

Additives include lactose, sucrose, corn starch, light maleic anhydride, microcrystalline cellulose, sorbitol, xylitol, mannite, and other excipients, carboxymethylcellulose, croscarmellose sodium, low degree of substitution. Hydroxypro Ability to add disintegrants such as pill cellulose, lubricants such as magnesium stearate, calcium stearate, and talc, as well as humectants, suspending agents, sweeteners, flavoring agents, flavoring agents, preservatives, etc. ,'it can.

Further, the GASN-containing pharmaceutical composition or the histamine H2 receptor antagonist-containing pharmaceutical composition of the present invention is capable of using a suitable solvent in granulation, and the solvent is a GASN force; There is no particular limitation as long as it is understood. Examples of the solvent include water, lower fatty alcohols, and aqueous solutions of these alcohols. The mixing ratio in the case of the aqueous solution of alcohol is not particularly limited. As lower fats and alcohols, linear or branched alcohols having 1 to 4 carbon atoms are preferable, and methanol and ethanol are particularly preferable.

The GASN-containing pharmaceutical composition or the histamine H2 receptor antagonist-containing pharmaceutical composition of the present invention is produced by granulating GASN and aldioxa by a wet granulation method. It is iJ ^ that GASN is mixed with an aldioxa and, if necessary, other additives and a binder and a solvent are used, whereby the adioxa and GASN are uniformly dispersed in each particle. As a result, the microstructure in each particle is easily brought into contact with GAZO and GASN, and a remarkable stabilizing effect of GASN is achieved.

For example, when using a fluidized bed granulation dryer, mix GASN, Ardioxa and excipients in a 5fE layer granulation dryer, spray an appropriate binder such as aqueous hydroxypropylcellulose solution, and granulate and dry. do it.

When granulating by extrusion granulation, crushing granulation, tumbling granulation, etc., mix other additives according to GASN and aldioxa, and granulate using appropriate amounts of binder and solvent. , Preferably dry.

In the histamine H 2 receptor antagonist-containing pharmaceutical composition of the present invention, the histamine H 2 receptor antagonist may be wet-granulated together with GASN and aldioxa, or GASN and aldioxa were previously wet-granulated. The granules and the hismin H2 receptor antagonist may be further formulated by an appropriate method.

For example, when using a bed granulation dryer, histamine H 2 receptor antagonist, G ASN, adioxa and an excipient may be mixed in a bed granulation dryer, sprayed with a suitable binder such as an aqueous hydroxypropyl cellulose solution, granulated and dried. Alternatively, mix GASN, Ardioxa and excipients in a layered granulation dryer, spray hydroxypide (appropriate combination such as aqueous solution of Pilssel or the like), granulate and dry, then granulate appropriately Then, a granule containing a His-Humin H2 receptor antagonist having the same particle size as that of the above-mentioned granulated product may be blended, and further formulated as required.

When granulating by extrusion granulation, crushing granulation, or ill road granulation, etc., histamine H2 receptor antagonist, GASN and aldioxa, and other additives as necessary Granulation using a suitable amount of a solvent and drying are preferred. Alternatively, the histamine H2 receptor antagonist or its granule is blended after mixing GAS N and other additives according to ^ and other additives, granulating and drying using an appropriate amount of a binder and a solvent, It may be further formulated as required.

The GASN-containing pharmaceutical composition or the histamine H2 receptor antagonist-containing pharmaceutical composition of the present invention can be obtained by the above-mentioned granulation method or through a further usual preparation process to obtain granules, powders, fine granules, tablets, It can be made into a dosage form suitable for oral administration such as pills, chew nore tablets and capsules.

The preparation thus produced is orally administered to the patient once to three times a day. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be more specifically described by way of examples. The present invention is not limited to these.

Illusion 1

Take 2 g of GASN, 100 g of Argioxa, 350 g of lactose and 122.5 g of corn starch, perform granulation and drying using a 10% hydroxypropylcellulose aqueous solution as a binder with an L¾ layer granulation dryer, and make up I got something. This composition was stable (see the test example described below).

Example 2

Take 2 g of GASN, 50 g of Ardioxa and 472.5 g of sorbitol, add 1 Using a 0% aqueous solution of hydroxypropylcellulose as a binder, granulation and drying were performed using a '^ -layer granulation dryer, to obtain a composition. This composition was stable (see the test examples described below).

麵 Example 3

Take 350 g of lactose and 122.5 g of corn starch, dissolve 2 g of GASN in an aqueous solution of 10-hydroxypropylcellulose, and disperse 4 g of force, aldioxa, as a binder. The mixture was granulated and dried to obtain a composition. This composition was stable when left for 1 month under the storage conditions of the example (40, relative humidity 75%).

Difficult case 4

Take 47.5 g of sorbitol, dissolve 2 g of GASN in a 10% aqueous solution of hydroxypropylcellulose, use a solution in which 2 g of force, aldioxa is dispersed as a binder, granulate with a bed granulation dryer, Drying was performed to obtain a composition. This composition was stable when left for 1 month under ^^ storage conditions (40, 75% relative).

Here, in MS Examples 1 to 4, the weight parts of Argioxiza with respect to 1 weight part of GASN are summarized in a table.

麵 Example 5

Take 2 g of GASN, 100 g of Ardioxa; 5 g of famotidine and 475 g of sorbitol, granulate and dry with a fluidized bed granulating dryer using a 10% aqueous solution of hydroxypropinolecellulose as a binder, Obtained.

Difficult case 6 Take 2 g of GASN, 50 g of aldioxa, 2.5 g of famotidine, 402.5 g of lactose and 125 g of corn starch, and granulate using a 7.5% hydroxypropylcellulose aqueous solution as a binder in a fluidized bed granulating dryer. After drying, the granules were obtained.

Difficult case 7

Take 50 g of Argioxa, 2.5 g of famotidine, 402.5 g of lactose, and 125 g of corn starch, and granulate and dry using a 10% polyvinylpyrrolidone aqueous solution in which 2 g of GASN is dissolved as a binder with a bed granulation dryer. Was carried out to obtain granules.

麯 Example 8

Take 2 g of GASN, 50 g of Ardioxa, 2.5 g of famotidine, 402.5 g of lactose, and 125 g of corn starch, knead with a 15% aqueous solution of hydroxypropylcellulose as a binder using a vertical mixer, and extrude. Granulation was performed with a granulator to obtain columnar granules. The capsules were dried by a fluidized bed granulator and filled into the first capsule by 300 mg in a capsule filling machine to obtain capsules.

Difficult case 9

2 g of GASN, 100 g of aldioxa, 10 g of famotidine and 50 g of lactose were taken, and granulated and dried using a 10% hydroxypropylcellulose aqueous solution as a binder in a layer granulation dryer to obtain fine granules. To this, 60 g of microcrystalline cellulose, 12.5 g of corn starch, 3 g of light gay anhydride, and 4 g of magnesium stearate are added, mixed for 10 minutes with a mixer, and 25 mg of 1 tablet with a tableting machine. Tablets were prepared.

mExample 10

Dissolve 2 g of GASN in 100 g of a 50% aqueous ethanol solution containing 10% hydroxypropylcellulose, add to 100 g of Aldioxa and 100 mannitol, knead with a vertical mixer, and dry with a fluid bed granulation dryer. This dried product is pulverized with a sample mill, and 10 g of famotidine and 360 g of sorbitol are taken. Using a 10-hydroxypropylcellulose aqueous solution as a binder, a layer granulation dryer is used. Then, granulation and drying were performed to obtain fine granules.

Case study 11

Dissolve 2 g of GASN in 100 g of a 50% aqueous methanol solution containing 10% hydroxypropylmethylcellulose, add 100 g of aldioxa and 100 g of lactose, dry with an optical mixer, and dry with a J¾ layer granulation dryer. The dried product is pulverized with a sample mill, and 5 g of famotidine, 100 g of crystalline cellulose, 10 g of corn starch, 1 g of light gay anhydride, and 2 g of magnesium stearate are added. A tablet of 33 Omg was made on a machine.

Dissolve 1 g of famotidine in 100 g of a 50-ethanol aqueous solution containing 12% hydroxypropynolecellulose, disperse 1 g of famotidine, add 100 g of argioxa and 100 g of lactose, mix with a vertical mixer, and use a fluid bed granulation dryer. , dry. The dried product was pulverized with a sample mill, and 370 g of sorbitol was taken. The mixture was granulated and dried in a 5-t layer dryer using a 10% aqueous solution of hydroxypropylcellulose as a binder to obtain granules. This was filled into the first capsule in 300 mg increments using a capsule filling machine to obtain a capsule.

Case 13

Dissolve 2 g of GASN in 100 g of a 50% aqueous ethanol solution containing 1590 polyvinylpyrrolidone, add to 100 g of ardioxa and 100 g of mannitol, knead the mixture with a single mixer, and dry with a J-layer granulation dryer. The dried product is pulverized with a sample mill, 360 g of xylitol is added, and a 10-hydroxypropylcellulose aqueous solution in which 10 g of famotidine is dispersed is used as a binder, and granulation and drying are performed using a layer granulation dryer. Agent was obtained. In the following comparative examples, no Ardioxa was blended.

Comparative Example 1

In Comparative Example 1, a composition corresponding to Example 1 is obtained. However, it is strongly different that Argioxa was not combined. GASN2g, lactose 350 g and corn siden 133 g of starch was taken, and granulated and dried using a fluidized bed granulating dryer using a 10% aqueous solution of hydroxypropylcellulose as a binder to obtain a composition.

Comparative Example 2

Comparative Example 2 corresponds to the stabilization method described in JP-A-58-154548, in which GASN is spray-dried and the solvent is distilled off.

472.5 g of sorbitol was taken, and granulation and drying were performed with a fluidized bed granulation dryer using an aqueous solution obtained by dissolving 2 g of GASN in a 10% aqueous solution of hydroxypropyl cellulose as a binder to obtain a composition.

Comparative Example 3

In Comparative Example 3, as a stabilizer, Sorbitole and sucralfate disclosed in JP-A-6-227972 were blended.

2 g of GASN, 250 g of sucralfate and 686 g of sorbitol were subjected to granulation and drying using a 10% aqueous solution of hydroxypropylcellulose as a binder with a USJ layer granulation dryer to obtain a composition. Industrial availability

In the present invention, a stable GASN-containing pharmaceutical composition can be provided by blending GASN and ardioxa and performing wet granulation.

Further, in the present invention, a pharmaceutical composition comprising a histamine H2 receptor antagonist, GASN and aldioxa, wherein at least histamine H2 receptor is contained in the granulated granules obtained by wet granulation of GASN and aldioxa. A histamine H2 receptor-containing pharmaceutical composition that has excellent therapeutic and preventive effects on gastrointestinal diseases such as gastric ulcer and acute / chronic gastritis, and is a commercially available drug. It is stable enough to withstand long-term storage. The stabilizing effect of the present invention will be described with reference to test examples.

Test example 1

Compositions of Examples 1 and 2, which are the pharmaceutical compositions containing GAS N of the present invention, and Comparative Examples Each of the compositions 1 to 3 was taken, sealed in a glass bottle, and stored in a thermostat at 40 and a relative humidity of 75%. The residual ratio of GASN after 2 months was measured by the HPLC method. The results, that is, the remaining ratio (%) of GASN at 40% and 75% relative humidity are shown in the table.

^ The compositions of Examples 1 and 2 in which Argioxa was blended showed that the residual ratio of GASN was dripped compared to the composition of Comparative Example 1 in which Algioxa was not blended. Therefore, the effect of the stabilization effect of Ardoxa, according to II, is according to Kafen. In addition, compared with the compositions of Comparative Examples 2 and 3 using a conventional stabilizing method or a stabilizer, the compositions of Examples 1 and 2 have more stabilized GASN.

Fiber example 2

In the same manner as in Test Example 1, the stabilizing effect of the compositions of Examples 9 and 10, which are the pharmaceutical compositions containing the hisminamine H2 receptor antagonist of the present invention, were confirmed.

From the above results, it was confirmed that the pharmaceutical composition containing a histamine H 2 receptor antagonist of the present invention was stable enough to withstand the distribution process as a commercial drug. Moreover, the therapeutic and preventive effects of gastrointestinal diseases such as gastric ulcer, acute and chronic gastritis, etc. of the pharmaceutical composition containing a His-amine H2 receptor antagonist of the present invention can be obtained by using a commonly used animal experimental model and Can be confirmed by clinical trials. One example is gastric ulcer treatment Miyata et foundation and clinical, 2 Volume 1, 1, No. 6, 9 5 - 1 0 5 page according to (1 9 8 7) test according to the latch Bok hydrochloric Asupirin ulcer model described in ^ ¹ Shinobu Was done.

Claims

The scope of the claims

1. Pharmaceutical composition containing stable 1,4-dimethyl-7-isopropinoleazulene-3-sodium sulfonate (hereinafter abbreviated as GASN), which is characterized in that it is blended with aldioxa and subjected to wet granulation. .

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a granulated product, and each granulated product contains GAS N and adioxa.

3. The pharmaceutical composition contains one or more particles wet-granulated, each particle containing GASN, and an aldioxa to stabilize the GASN, and the GASN and the aldioxa power within each particle. 3. The pharmaceutical composition according to claim 1, which is uniformly dispersed.

4. The pharmaceutical composition according to claim 1, wherein the content of the aldioxa is 0.01 to 250 parts by weight per 4 parts of GASN.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the content of the algioxa is 0.5 to 100S4 parts based on the GASN lltt part.

6. A method for producing a stable GASN-containing pharmaceutical composition by blending GASN and aldioxa and performing wet granulation.

7. A pharmaceutical group formed containing the histamine H ² receptor antagonist and GASN and Arujiokisa, that at least GASN and Arujiokiza are those contained in the granulated product in which is granulated by wet granulation A pharmaceutical composition containing a histamine H2 receptor antagonist.

8. The pharmaceutical composition according to claim 7, wherein the histamine H2 receptor antagonist is famotidine.

9. The pharmaceutical composition comprises one or more wet-granulated particles, each particle comprising at least GASN, and an aldioxa to stabilize the GASN, and the GASN and aldioxa power within each particle. The pharmaceutical composition according to claim 7 or 8, which is uniformly dispersed.

10. Argioxa is used at least 0.01 parts by weight per 250 parts by weight of GASN The pharmaceutical composition according to claim 7, 8 or 9, wherein the pharmaceutical composition is contained in an amount of not more than part by weight.

11. The pharmaceutical composition according to any one of claims 7 to 10, wherein the composition contains from 0.5 to 100 parts by weight of aldoxa per 1 part by weight of GASN.

12. A histamine H2 receptor antagonist is prepared by mixing a histamine H2 receptor antagonist with GASN and aldioxa and granulating by wet abrasion, or by mixing GASN and aldioxa and granulating by a wet granulation method. A method for producing a pharmaceutical composition containing a His Hismin H2 receptor antagonist.